Comparing multilayer brain networks between groups: Introducing graph metrics and recommendations

There is an increasing awareness of the advantages of multi-modal neuroimaging. Networks obtained from different modalities are usually treated in isolation, which is however contradictory to accumulating evidence that these networks show non-trivial interdependencies. Even networks obtained from a single modality, such as frequency-band specific functional networks measured from magnetoencephalography (MEG) are often treated independently. Here, we discuss how a multilayer network framework allows for integration of multiple networks into a single network description and how graph metrics can be applied to quantify multilayer network organisation for group comparison. We analyse how well-known biases for single layer networks, such as effects of group differences in link density and/or average connectivity, influence multilayer networks, and we compare four schemes that aim to correct for such biases: the minimum spanning tree (MST), effective graph resistance cost minimisation, efficiency cost optimisation (ECO) and a normalisation scheme based on singular value decomposition (SVD). These schemes can be applied to the layers independently or to the multilayer network as a whole. For correction applied to whole multilayer networks, only the SVD showed sufficient bias correction. For correction applied to individual layers, three schemes (ECO, MST, SVD) could correct for biases. By using generative models as well as empirical MEG and functional magnetic resonance imaging (fMRI) data, we further demonstrated that all schemes were sensitive to identify network topology when the original networks were perturbed. In conclusion, uncorrected multilayer network analysis leads to biases. These biases may differ between centres and studies and could consequently lead to unreproducible results in a similar manner as for single layer networks. We therefore recommend using correction schemes prior to multilayer network analysis for group comparisons

Regulatory T cell DNA methyltransferase inhibition accelerates resolution of lung inflammation

Acute respiratory distress syndrome (ARDS) is a common and often fatal inflammatory lung condition without effective targeted therapies. Regulatory T cells (Tregs) resolve lung inflammation, but mechanisms that enhance Tregs to promote resolution of established damage remain unknown. DNA demethylation at the forkhead box protein 3 (Foxp3) locus and other key Treg loci typify the Treg lineage. To test how dynamic DNA demethylation affects lung injury resolution, we administered the DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine (DAC) to wild-type (WT) mice beginning 24 hours after intratracheal LPS-induced lung injury. Mice that received DAC exhibited accelerated resolution of their injury. Lung CD4+CD25hi Foxp3+ Tregs from D AC-treated WT mice increased in number and displayed enhanced Foxp3 expression, activation state, suppressive phenotype, and proliferative capacity. Lymphocyte-deficient recombinase activating gene-1-null mice and Treg-depleted (diphtheria toxin-treated Foxp3DTR) mice did not resolve their injury in response to DAC. Adoptive transfer of 2 ×105 DAC-treated, but not vehicle-treated, exogenous Tregs rescued Treg-deficient mice from ongoing lung inflammation. In addition, in WT mice with influenza-induced lung inflammation, DAC rescue treatment facilitated recovery of their injury and promoted an increase in lung Treg number. Thus, DNA methyltransferase inhibition, at least in part, augments Treg number and function to accelerate repair of experimental lung injury. Epigenetic pathways represent novel manipulable targets for the treatment of ARDS

The role of potential vorticity anomalies in the Somali Jet on Indian summer monsoon intraseasonal variability

The climate of the Indian subcontinent is dominated by rainfall arising from the Indian summer monsoon (ISM) during the summer season (June to September). Intraseasonal variability during the monsoon is characterized by periods of heavy rainfall interspersed by drier periods, known as active and break events respectively. Understanding and predicting such events is of vital importance for forecasting human impacts such as water resources. The Somali Jet is a key regional feature of this circulation. In the present study, we find that the spatial structure of Somali Jet potential vorticity (PV) anomalies varies considerably during active and break periods. Analysis of these anomalies shows a mechanism whereby sea surface temperature (SST) anomalies propagate north/northwestwards through the Arabian Sea, caused by a positive feedback loop joining anomalies in SST, convection, modification of PV by diabatic heating and mixing in the atmospheric boundary layer, wind stress curl, and upwelling processes. The feedback mechanism is consistent with observed coupled ocean-atmosphere system variability timescales of approximately 20 days. This research suggests that better understanding and prediction of monsoon subseasonal variability in the South Asian monsoon may be gained by analysis of the day-to-day dynamical evolution of PV in the Somali Jet

Study of MicroRNA-34a mediated post transcriptional regulation of MDM4

MDM4 is an important negative regulator of the tumor suppressor p53. In normal unstressed cells the activity of p53 is kept under control by MDM4 and its homologue MDM2. MDM4 is said to possess oncogenic potential based on the evidence of its overexpression in many cancers. Until recently it was believed MDM4 is constitutively transcribed; however a decrease in full length MDM4 in response to genotoxic stress was observed paving way for exploring the mechanism responsible for this. It was observed miR-34a a member of the miR34 family which is a direct transcriptional targets of p53 could have a potential role in regulation of MDM4 expression. The 3\u27untranslated region of MDM4 was also seen to contain several miR-34a binding sites. However reporter assays with select regions of the 3\u27UTR revealed that the 3\u27UTR was unresponsive to miR-34a mediated regulation. Reassessment of the MDM4 gene revealed presence of a potential miR-34a regulatory site in the protein coding exon eleven of MDM4. This site was further considered to check for functionality in response to miR-34a modulation. A reporter with the miR-34a site from the coding region was constructed. This reporter was responsive to overexpression or inhibition of endogenous miR-34a in H1299 and MCF7 cells respectively ascertaining the functionality of this site. A SNP leading to an A to C transversion in the seed region of this miR-34a site in the exon 11 was predicted to disrupt responsiveness to miR-34a. We confirmed this by creating point mutants and performing reporter assays. This study was designed to understand the regulation of MDM4 in absence of DNA damage conditions. Understanding the role of miR-34a in regulation of MDM4 will pave way for designing specific therapeutic strategy for reactivation of p53 via inhibition of MDM4 in cancer that overexpress MDM4 and retain wild type p53

MicroRNA-34a Modulates MDM4 Expression via a Target Site in the Open Reading Frame

Background MDM4, also called MDMX or HDMX in humans, is an important negative regulator of the p53 tumor suppressor. MDM4 is overexpressed in about 17% of all cancers and more frequently in some types, such as colon cancer or retinoblastoma. MDM4 is known to be post-translationally regulated by MDM2-mediated ubiquitination to decrease its protein levels in response to genotoxic stress, resulting in accumulation and activation of p53. At the transcriptional level, MDM4 gene regulation has been less clearly understood. We have reported that DNA damage triggers loss of MDM4 mRNA and a concurrent increase in p53 activity. These experiments attempt to determine a mechanism for down-regulation of MDM4 mRNA. Methodology/Principal Findings Here we report that MDM4 mRNA is a target of hsa-mir-34a (miR-34a). MDM4 mRNA contains a lengthy 3′ untranslated region; however, we find that it is a miR-34a site within the open reading frame (ORF) of exon 11 that is responsible for the repression. Overexpression of miR-34a, but not a mutant miR-34a, is sufficient to decrease MDM4 mRNA levels to an extent identical to those of known miR-34a target genes. Likewise, MDM4 protein levels are decreased by miR-34a overexpression. Inhibition of endogenous miR-34a increased expression of miR-34a target genes and MDM4. A portion of MDM4 exon 11 containing this 8mer-A1 miR-34a site fused to a luciferase reporter gene is sufficient to confer responsiveness, being inhibited by additional expression of exogenous mir-34a and activated by inhibition of miR-34a. Conclusions/Significance These data establish a mechanism for the observed DNA damage-induced negative regulation of MDM4 and potentially provide a novel means to manipulate MDM4 expression without introducing DNA damage

The effect of variation in inter-appointment time on the incidence of post-operative pain in single-visit versus two visit endodontics: An in vivo study

Aim: This clinical study was conducted to observe and note the effect of variation in inter-appointment time period on the incidence of post-operative pain following single-visit versus two visit endodontics in vital and nonvital teeth with and without periapical radiolucency. Materials and Methods: A total of 80 adult patients requiring root canal therapy in anterior and premolar teeth were selected for this study and divided into four groups. Two sitting root canal treatment was carried out in three groups (Group 1 with inter-appointment time of 72 h, Group 2 with inter-appointment time of 48 h and Group 3 with inter-appointment time of 24 h) and single sitting root canal treatment was carried out in one group (Group 4). The subjects were recalled after 2 weeks and instructed to fill out a series of self-report questionnaires for responses about pain in the interim after 1 day, 2 day, 3 day, 1 week and 2 weeks. Results: Though comparison of pain incidence in different groups was not statistically significant, there was a greater tendency for post obturation pain incidence in teeth treated with single sitting root canal therapy and those with inter appointment period of 72 h. Results obtained were comparable to those obtained by several investigators

Comparison of the effect of ethylenediamine tetra-acetic acid, chlorhexidine, etidronic acid and propolis as an irrigant on the microhardness of root dentin: An in vitro study

Aim: This in vitro study was carried out to compare of the effect of 17% ethylenediamine tetra-acetic acid (EDTA), 2% chlorhexidine (CHX), 18% etidronic acid (HEBP), and 4% propolis as an irrigant on the microhardness of root dentin. Materials and Methods: The sample size for the study was 100. Each specimen consisted of a longitudinally sectioned half of a root of a single-rooted tooth which was embedded in acrylic resin. The prepared specimens were divided randomly into five groups of twenty specimens each. Each group was treated with the irrigants to be tested. Group I was the control - the specimens were treated with distilled water. The specimens in Group II were treated with sodium hypochlorite (NaOCl) followed by EDTA. Specimens in Group III were treated with NaOCl followed by CHX. Specimens in Group IV were treated with NaOCl followed by HEBP, and specimens in Group V were treated with NaOCl followed by propolis. Following this, all the specimens were placed on the Vickers hardness tester and three readings were taken for each specimen. An average reading was obtained for each group. The results were tabulated and statistically analyzed to determine which of the irrigant solutions had the least effect on the microhardness of root dentin. Results: Eighteen percent HEBP had the least effect on the root dentin microhardness, followed by 4% propolis and 2% CHX. Seventeen percent EDTA showed maximum effect on the microhardness of the dentin. Conclusion: Under the limitations of this study, 18% HEBP and 4% propolis show promise for use as irrigants because of less detrimental effect on the hardness of root dentin. More studies are needed on demineralization depth and the sealability of resin sealers in the radicular dentin after the use of propolis and HEBP